Sun et al. BMC Complementary and Alternative Medicine (2016) 16:201 DOI 10.1186/s12906-016-1174-1 RESEARCH ARTICLE Clinical effects of a standardized Chinese herbal remedy, Qili Qiangxin, as an adjuvant treatment in : systematic review and meta-analysis Open Access Jin Sun 1, Kang Zhang 1, Wen-Jing Xiong 1, Guo-Yan Yang 1, Yun-Jiao Zhang 1, Cong-Cong Wang 1, Lily Lai 2, Mei Han 1, Jun Ren 1, George Lewith 2 and Jian-Ping Liu 1,3* Abstract Background: Qili Qiangxin capsule is a standardized Chinese herbal treatment that is commonly used in China for (HF) alongside conventional medical care. In 2014, Chinese guidelines for the treatment of chronic HF highlighted Qili Qiangxin capsules as a potentially effective medicine. However, there is at present no high quality review to evaluate the effects and safety of Qili Qiangxin for patients with HF. Methods: We conducted a systematic review and meta-analysis and followed methods described in our registered protocol [PROSPERO registration: CRD42013006106]. We searched 6 electronic databases to identify randomized clinical trials (RCTs) irrespective of blinding or placebo control of Qili Qiangxin used as an adjuvant treatment for HF. Results: We included a total of 129 RCTs published between 2005 and 2015, involving 11,547 patients, aged 18 to 98 years. Meta-analysis showed no significant difference between Qili Qiangxin plus conventional treatment and conventional treatment alone for mortality (RR 0.53, 95 % CI 0.27 to 1.07). However, compared with conventional treatment alone, Qili Qiangxin plus conventional treatment demonstrated a significant reduction in major cardiovascular events (RR 0.46, 95 % CI 0.34 to 0.64) and a significant reduction in re-hospitalization rate due to HF (RR 0.49, 95 % CI 0.38 to 0.64). Qili Qiangxin also showed significant improvement in cardiac function measured by the New York Heart Association scale (RR 1.38, 95 % CI 1.29 to 1.48) and quality of life as measured by Minnesota Living with Heart Failure Questionnaire (MD 8.48 scores, 95 % CI 9.56 to 7.39). There were no reports of serious adverse events relating to Qili Qiangxin administration. The majority of included trials were of poor methodological quality. Conclusions: When compared with conventional treatment alone, Qili Qiangxin combined with conventional treatment demonstrated a significant effect in reducing cardiovascular events and re-hospitalization rate, though not in mortality. It appeared to significantly improve quality of life in patients with HF and data from RCTs suggested that Qili Qiangxin is likely safe. This data was drawn from low quality trials and the results of this review must therefore be interpreted with caution. Further research is warranted, ideally involving large, prospective, rigorous trials, in order to confirm these findings. Keywords: Qili Qiangxin capsule, Chinese herbal medicine, Heart, Randomized clinical trials, Systematic review, Meta-analysis * Correspondence: jianping_l@hotmail.com; LiuJP@bucm.edu.cn 1 Center for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China 3 National Research Centre in Complementary and Alternative Medicine (NAFKAM), Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway Full list of author information is available at the end of the article 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Sun et al. BMC Complementary and Alternative Medicine (2016) 16:201 Page 2 of 13 Background Heart (HF) is a serious and increasingly prevalent worldwide public health problem and has become a major cause of mortality and morbidity [1]. HF is the most common cause of hospitalization in people aged 65 and older [2] and survival rates are reportedly worse than in cancer [3]. According to the European Society of Cardiology (ESC), approximately 26 million people worldwide suffer from HF and which affects 10 % of people over the age of 70, a prevalence which is expected to rise in coming years. HF is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood from the heart. Cardinal manifestations include dyspnea and fatigue, which can limit exercise tolerance as well as create fluid retention, and which may lead to pulmonary and peripheral edema [4]. Furthermore, quality of life (QOL) for patients can be adversely impacted owing to sleep-disordered breathing, cognitive dysfunction and neuropsychological disturbances. Conventional medical care for HR typically involves oxygen therapy, diet, diuretics, angiotensin-converting enzyme inhibitors (ACEI) or beta-blockers [5]. Previous research has estimated that the total estimated direct and indirect cost of HF in the US in 2005 was approximately $27.9 billion, with approximately $2.9 billion alone being spent annually on drugs [6]. Despite this significant annual spend, HF continues to be associated with poor prognosis, with absolute mortality rate remaining approximately 50 % within 5 years of initial diagnosis [7]. It is clear that the effectiveness of available care is limited and which warrants further research into optimizing current treatments. In the recent 2014 Chinese guidelines for treatment of chronic HR, a Chinese herbal remedy, Qili Qiangxin capsules, was mentioned as a potentially effective treatment [8]. Qili Qiangxin capsule is a standardized Chinese herbal treatment that is widely used in China for HF patients and which is frequently administered alongside conventional medical care. It is prepared from 11 Chinese herbs including astragali radix, ginseng radix et rhizoma, aconite lateralis radix preparata, salvia miltiorrbiza radix et rhizoma, semen descurainiae lepidii, alismatis rhizoma, polygonati odorati rhizoma, cinnamomi ramulus, carthami flos, periploca cortex, and citri reticulatae pericarpium. Previous research has suggested that Qili Qiangxin may have a role in the treatment of HF through a number of different mechanisms, for example reducing N-terminal pro-brain natriuretic peptide (NT-proBNP), high levels of which are associated with cardiac ventricular volume and pressure overload [9]. In a study on rats with myocardial infarction (MI), Qili Qiangxin induced heart muscle regeneration and improved cardiac function through regulating the balance between tumor necrosis factor (TNF)-α and interleukin (IL)-10, factors closely associated with inflammatory processes in HF [10]. This suggests promise in this area of research which may be of significant interest to the international medical community and which warrants a robust review of the current evidence to date. A number of systematic reviews have been published in this area. However, all have been published in Chinese and have various shortcomings such as insufficient searches, inappropriate outcome selection and lack of quality assessment, leading us to question the scientific rigor of the results and subsequent recommendations [11 16]. The aim of this study was to evaluate the effects and safety of Qili Qiangxin for patients with HF by conducting a systematic review and meta-analysis. Methods The method used to conduct this systematic review has been previously published in a registered protocol [PROSPERO registration: CRD42013006106]. This review was constructed using the PRISMA guidelines (Additional file 1). Search strategy The following electronic databases were searched from date of inception to March 2015: PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (Issue January, 2015), China National Knowledge Infrastructure (CNKI), VIP Database, Sino- Med Database, and Wanfang Database. We used the following search terms: ( Qili Qiangxin OR qiliqiangxin OR qiangxinli ) and ( OR cardiac OR heart decompensation ). We searched for trials from mainstream registries including Current Controlled Trials (http://www.controlled-trials.com), the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; http://apps.who.int/trialsearch/), ClinicalTrials.gov trials registry (http://www.clinicaltrials. gov), the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au), and Centre Watch (http:// www.centerwatch.com). We also hand-searched the reference lists of all full text papers for additional relevant reports. No language restrictions were imposed. Inclusion criteria We accepted RCTs regardless of blinding procedures and included only parallel design studies. Only human studies were included in this review and we required the use of internationally-accepted criteria for diagnosis of HF. We placed no other requirements of the participant population in terms of gender, age, etiology, ethnic group, severity or course of disease. Only Qili Qiangxin capsules, composed of the aforementioned 11 Chinese herbs, were accepted as the intervention. This could be used alone or alongside appropriate control treatments such as placebo, conventional treatment or no treatment, and trials with any other Chinese herbal medicine in control group will be excluded. Our primary outcome
Sun et al. BMC Complementary and Alternative Medicine (2016) 16:201 Page 3 of 13 measures were all-cause mortality or cardiovascular mortality due to HF, major cardiovascular events such as MI, outpatient visits, hospitalizations or re-admission for HF. Secondary outcomes measures were quality of life (QOL) measured by Minnesota Living with Heart Failure Questionnaire (MLHFQ), New York Heart Association (NYHA) functional classification, echocardiography measurements, six-minutes walking distance (6MWD), plasma amino-terminal pro-brain natriuretic peptide (NT-pro-BNP). We also collected safety and adverse eventsdata.weincludedonlyrctsreportingoneor more of these outcomes. Data extraction and quality assessment Two authors (from J Sun, K Zhang, WJ Xiong, and YJ Zhang) independently identified articles for eligibility with any disagreements resolved through discussion with a third party (JP Liu). Two authors independently extracted data and which included patient characteristics, details of the intervention and control groups, outcome measures and main results. The same process was used to assess the methodological quality of included RCTs using the risk of bias tool as described in the Cochrane Handbook for Systematic Reviews of Interventions [17]. This process requires seven criteria to be assessed: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, free of selective reporting, and other bias. Strategy for data synthesis Statistical analyses were performed by using RevMan 5.2 software (The Cochrane Collaboration). Pooled risk ratio (RR) with 95 % confidence interval (CI) of dichotomous outcomes was used to estimate report effect. Continuous data was presented as mean difference (MD) with 95 % CI. We used a fixed effect model unless there was evidence of heterogeneity. Heterogeneity was assessed using both the Chi-squared test and the I-squared statistic, and we considered an I-squared value greater than 50 % to be indicative of substantial heterogeneity. If missing data from the original trials are available, intention-to-treat analysis will be applied for primary outcome. Results Description of studies Our search in March 2015 from six databases and other sources identified 1,390 potentially eligible articles. After removing duplicates and reviewing full text articles, we eventually included 129 randomized clinical trials published as 131 articles (Fig. 1). All 129 studies were included in our qualitative synthesis and of these, 117 studies were eligible for our meta-analysis. Study characteristics Included trials were published between 2005 and 2015 with a larger proportion of trials published in 2013 (n =41 trials, 31.78 %) and 2012 (n = 23 trials, 17.83 %). The 129 trials involved 11,547 patients diagnosed with HF with an age range of 18 to 98 years. Sixteen trials enrolled only elderly patients over the age of 60 (n =16, 12.40 %). The majority of trials included both male and female patients (n = 127 trials, 98.45 %). Two trials included only male patients (Wei XB 2013, Miao S 2013); two trials provided gender details only for participants who completed the trial (Li XL 2013, Kuang JB 2008). 58.23 % of total populations were male except one trial failed to provide gender detail (Tao X 2011). Included trials used the following diagnostic criteria: American College of Cardiology/American Heart Association (ACC/AHA) guidelines, European Society of Cardiology (ESC) guidelines, World Health Organization/ International Society and Federation of Cardiology (WHO/ISFC) guidelines, World Health Organization/ International Society of Hypertension (WHO/ISH) guidelines, Chinese Medical Association (CMA) guidelines, guidelines issued by Ministry of Health (MoH) in China, Framingham criteria, or textbook criteria which were consistent with internationally-used diagnostic criteria. One hundred seventeen trials (s1-s118, Additional file 2) involving 10,170 patients compared Qili Qiangxin capsules plus conventional treatment to conventional treatment alone. Three trials (s119-s121, Additional file 2) involving 702 patients compared Qili Qiangxin capsule plus conventional treatment to placebo plus conventional treatment. Nine trials (s122-s131, Additional file 2) included 675 patients comparing Qili Qiangxin capsules plus conventional treatment to recommended pharmaceuticals (including thiazide diuretics, benazepril, captopril, metoprolol, irbesartan, hydrochlorothiazide and digoxin plus conventional treatment). Almost all patients in the included trials presented with comorbidities such as hypertension, hypotension, valvular heart disease, pulmonary heart disease, cardiomyopathy, diabetes mellitus, chronic renal insufficiency, coronary heart disease, acute MI and sinus bradycardia. The duration of treatment ranged from 1 to 12 months, and the most commonly adopted was 1 month (n = 54 trials). Nineteen trials had 6 or more months of treatment. The main outcome in the majority of trials was reported to be left ventricular ejection fraction (LVEF) (n = 91 trials). Other primary outcomes adopted included mortality (n = 6 trials), major cardiovascular events (n = 3 trials) or re-hospitalization (n =9 trials). Details of each study are listed in Table 1.
Sun et al. BMC Complementary and Alternative Medicine (2016) 16:201 Page 4 of 13 Fig. 1 Flow chart of study searching and selection Methodological quality of included trials The methodological quality of included trials was generally low as most failed to provide protocols (Additional file 3). Nineteen trials (n = 2388 participants, 20.68 %) were judged as low risk on random sequence generation. Of these twenty, 17 trials used random number tables (n = 1774 participants, 72.29 %), one trial used statistical software (n = 512 participants, 21.44 %) and one trial used drawing lots. Only one (Li XL 2013) trial reported allocation concealment was judged as low risk; one trial (Yang F 2007) described using an envelope but failed to provide further details and was subsequently judged as presenting with unclear risk of bias. We judged five trials on the use of blinding methods. Of these, three double-blind placebo controlled trials (Yu JH 2008, Li XL 2013, Yu JH 2008) were judged as low risk (n = 702 participants, 6.08 %). For the remaining two trials, one single-blind trial (Guo WB 2013) and one double-blind trial (Wei XB 2013) did not mention who was blinded and were judged as unclear risk. Besides, only one trial (Li XL 2013) reported the blinding of outcome assessment (n = 512 participants, 4.43 %). Overall six trials reported patient attrition (n =948 participants, 8.21 %). Of these, three trials (Chen WQ 2012, Fu JZ 2012, Sun LP 2007) reported no drop-out. Three trials (Guo P 2014, Li XL 2013, Kuang JB 2008) described the occurrence of attrition, one (Li XL 2013) used a flow chart to describe patient attrition in the two parallel groups throughout the whole study and adopted intention to treat (ITT) analysis, and one (Kuang JB 2008) was judged as high risk as the authors failed to provide drop-out reasons in text. The remaining trials reported the same number of participants between the baseline and data analyzed, except one study (Guo WB 2013) which reported six cases less than the number at baseline without providing further explanation. Twenty-four trials failed to report all outcomes listed in the methods. The remaining trials reported all outcomes
Sun et al. BMC Complementary and Alternative Medicine (2016) 16:201 Page 5 of 13 Table 1 Characteristics of included studies ID (Author year) Disease Setting (in/out patients) Diagnosis criteria Sample size Age-T Age-C Men-% Course of treatment Bai LQ 2013 HF in NYHA 40 45 ± 3.7 52 ± 4.2 57.5 3M Cai RF 2013 CHF NA CMA 2009; MoH 2002; 50 52-80 52-81 54 4W Framingham criteria; NYHA Cai YP 2013 CHF in or out Framingham criteria; NYHA 108 73.2 ± 11.5 60.19 6M Chen L 2009 CHF in ACC/AHA 1995; MoH 2002; 61 67.2 ± 11.5 63.1 ± 13.8 57.38 4W NYHA Chen TC 2013 CHF NA CMA 2007; NYHA 52 71-92 68-91 53.85 4W Chen WQ 2012 CHF in or out CMA 2007; NYHA 120 58 ± 14 57 ± 14 59.17 6M Chen XH 2014 HF NA CMA 2014 60 63 ± 10 62 ± 11 52.17 6M Cheng XD 2013 ischemic heart in ACC/AHA criteria; NYHA 90 56.4 ± 6.2 54.2 ± 5.9 55.56 6W Cui LL 2012 CHF in CMA 2007; NYHA 68 59.41 ± 9.68 58.6 ± 7.71 48.53 5M Dai JX 2013 chronic congestive NA Guidelines for the Diagnosis and Treatment of Cardiovascular Disease 2006 100 70.2 58 4W Ding LB 2010 HF in Internal Medicine 2004; MoH 2002 Ding SY 2013 CHF NA Practical Internal Medicine 2001; NYHA Dong MX 2013 Du YK 2014 chronic congestive diastolic heart in Practical Internal Medicine 2001; NYHA 43 45 ± 12.2 42 ± 11.3 55.81 2M 72 48-82 51-79 45.83 4W 114 71.5 59.65 4W out CMA 2007 102 60-86 59-82 39.22 30D Duan JH 2010 CHF NA Clinical Cardiology 1996 61 63.4 ± 10.3 61.5 ± 8.7 72.13 3M Fan J 2013a CHF NA Internal Medicine 2008; NYHA 86 68.1 ± 9.5 68.7 ± 9.6 55.81 2M Feng QT 2013 chronic congestive out Framingham criteria 42 55.6 ± 10.32 54.66 ± 10.41 59.52 6M Fu JZ 2012 CHF Internal Medicine 2004; NYHA 60 77.3 ± 10.2 78.0 ± 10.1 58.33 3M Gao JB 2011 chronic congestive in or out MoH 2002 167 58 ± 11 58.08 4W Gu XM 2009 CHF in or out AHA criteria 38 52 ± 9 48 ± 10.6 68.42 2M Gu XM 2013 CHF in or out ACC/AHA 2005; NYHA 65 57 ± 18.5 56 ± 16 66.15 4W Gu YY 2012 CHF in or out NYHA 100 65.5 ± 10.1 62.3 ± 12.5 58.57 6M Guan SY 2012 CHF NA Consensus for diagnosis and treatment of with normal ejection fraction in China 2010 82 56 ± 13 54 ± 13 42.68 8W Guan SY 2013 CHF NA CMA 2007 72 55 ± 12 54 ± 13 52.78 12W Guo P 2014 CHF NA ACC/AHA criteria; NYHA 90 71.6 ± 4.5 72 ± 3.5 58.7 3M Guo SL 2011 chronic congestive in CMA 2007 120 60-80 60 3M Guo WB 2013 chronic congestive in CHF criteria 1979 70 61.5 ± 9.12 57.4 ± 8.97 57.14 8W Hu B 2013 CHF in or out Framingham criteria 80 39-75 36-76 78.75 3M Huang B 2010 chronic congestive NA Framingham criteria; NYHA 100 61.2 ± 11.8 60.8 ± 12.5 60 6M Huang YQ 2012 chronic congestive NA Internal Medicine 2004 46 60 ± 7.5 58 ± 7.8 47.83 4W Huang Z 2014 CHF in or out CMA 2007; NYHA 60 35-74 35-74 58.33 12W
Sun et al. BMC Complementary and Alternative Medicine (2016) 16:201 Page 6 of 13 Table 1 Characteristics of included studies (Continued) Jin Y 2012 derived from ischemic cardiomyopathy NA ICM criteria (Felker GM) 2002; NYHA 100 62.0 ± 15.2 63.0 ± 13.9 47 12W Jing GJ 2009 CHF in or out WHO criteria; CMA 2002; 60 62.0 ± 3.5 63 ± 4.0 58.33 4W MoH 2002 Kuang JB 2008 CHF NA ESC criteria 106 71.6 45.16 8W Li DW 2013 chronic congestive in NYHA 78 66 51.28 12W Li GM 2011 chronic congestive in or out Framingham criteria; NYHA 120 72.5 71.8 56.67 4W Li LC 2013 derived from ischemic cardiomyopathy NA NYHA 110 61 ± 13 63 ± 12 54.55 4W Li P 2011 CHF in or out CMA 2002;NYHA 76 66.1 ± 7.8 66.3 ± 7.2 59.21 3M Li Q 2014 HF NA NYHA 120 71.4 ± 8.0 70.2 ± 7.1 70.59 6M Li RY 2010a CHF NA NYHA 86 68.4 ± 1.3 68.1 ± 1.3 67.44 4W Li SQ 2014 CHF in or out CMA 2007; NYHA 147 41.2 ± 12.5 39.8 ± 13.2 40.82 2M Li SZ 2009 congestive heart NA NYHA 39 62 ± 7 56.41 4W Li T 2010 CHF in Boston criteria; NYHA 44 56 ± 14 56.82 4W Li WY 2013 CHF NA Internal Medicine 2008; NYHA 90 71 ± 4.6 73 ± 4.2 57.78 4W Li XL 2013 CHF NA CMA 2007; NYHA 512 56.98 ± 11.59 57.53 ± 11.05 75.36 12W Li YH 2013 CHF NA NYHA 80 67.3 ± 11.6 70 3M Li YX 2012 diastolic in or out ESC criteria; MoH 2002 100 61.6 ± 5.1 61.4 ± 5.4 43 6M Li YX 2013 CHF NA ESC 2007; MoH 2002; 80 61.6 ± 5.1 61.4 ± 5.4 46.25 12M Collateral Disease Theory 2006 Lin JH 2008 CHF in or out Clinical Cardiology 1999; NYHA 80 58 ± 12 60 4W Lin ZJ 2010 derived from ischemic cardiomyopathy NA WHO/ISFC 1980; NYHA 60 40 ± 13 38 ± 12 45 6M Liu HL 2008 CHF NA Guidelines for Cardiovascular 86 32.9 ± 4.1 33.1 ± 3.2 52.33 4W Disease 2005; NYHA Liu J 2008 derived from ischemic cardiomyopathy NA WHO/ISFC 1980; NYHA 41 41 ± 11 40 ± 11 60.98 6M Liu LX 2014 HF NA PracticalInternalMedicine2009 60 64.4 ± 11.5 64.5 ± 11.3 61.67 12W Liu SJ 2009 CHF in or out Clinical Cardiology 1996; 45 68.2 ± 7.6 66.8 ± 8.2 60 4W MoH 2002; NYHA Liu T 2013 HF NA NYHA 95 63.7 ± 7.4 65.7 ± 7.6 71.58 4W Liu TR 2010 CHF NA NYHA 84 46-68 45-70 63.1 8W Liu WJ 2007 ischemic in Felker's criteria 60 66 ± 10 65 ± 11 70 4M cardiomyopathy Liu XC 2008 refractory heart NA NYHA 120 56-79 58-78 80.83 30D Liu XC 2011 CHF in or out AHA criteria; NYHA 80 56.9 ± 7.3 57.0 ± 7.6 65 8W Liu XG 2013 CHF in or out AHA criteria; NYHA; 60 61.2 ± 11.8 60.8 ± 12.5 58.33 3M MoH 2002 Liu XM 2010 HF NA ACC/AHA criteria; NYHA 76 65-82 52.63 3M Liu XM 2013 CHF NA CMA 2007 64 69 ± 11 68 ± 12 57.81 4W Liu YJ 2012 HF in or out Clinical Cardiology; NYHA 60 78-90 76-92 68.33 30D Long F 2009 CHF in Clinical Cardiology 1996; CMA 2002; NYHA 110 20-73 18-70 53.64 4W
Sun et al. BMC Complementary and Alternative Medicine (2016) 16:201 Page 7 of 13 Table 1 Characteristics of included studies (Continued) Lu JP 2012 CHF in CMA 2007; NYHA 60 73.2 ± 12.5 72.9 ± 11.8 65 24W Luo Q 2013 chronic congestive in NYHA 60 62.5 ± 13.0 64.5 ± 12.2 56.67 3M Ma AP 2013 CHF NA NYHA 96 66.28 ± 4.92 65.84 ± 5.06 56.25 6M Ma FF 2008a CHF in Boston criteria 1985; NYHA 120 65.4 64.6 46.67 4W Ma FF 2008b CHF in Boston criteria 1985; NYHA 65 64.1 ± 17.2 46.15 4W Ma L 2010 CHF in or out ESC 1995; NYHA; MoH 2002 117 52.3 ± 9.2 50.1 ± 10.5 61.54 4W Ma RX 2014 CHF in CMA 2007 120 62 ± 12 60 ± 11 65.75 4W Miao S 2013 HF NA NYHA 102 77.2 ± 6.1 100 2M Niu LY 2012 CHF NA ACC/AHA criteria; NYHA; 60 63.2 ± 4.1 60.8 ± 5.4 63.33 4W MoH 2002 Pang XM 2008 CHF NA Framingham criteria 31 66 ± 12 48.39 4W Qiu X 2013 CHF NA NYHA 60 62 ± 4.2 60 ± 3.2 66.67 3M Rao LZ 2012 CHF NA CMA 2007; NYHA 80 65 ± 15 64 ± 14 51.25 4W Shen R 2010 HF in NYHA 62 74 ± 5 74 ± 7 77.42 28D Shen XR 2014 CHF in or out ACC/AHA criteria; NYHA 122 62 ± 6 66.45 12M Shi CP 2013 CHF in ISFC/WHO 1979; NYHA 120 64.5 ± 6.2 67.5 3M Su HM 2007 chronic congestive in Framingham criteria; 70 55.7 54.6 60 30D NYHA 1994 Su LJ 2012 CHF in or out CMA 2002; Practical Internal 69 NA NA 65.22 8W Medicine 2001; NYHA Su RY 2013 CHF NA CMA 2007; NYHA 86 69 46.51 4W Sun LP 2007 chronic congestive in NYHA 60 62 ± 12 63.33 12W Tang SY 2013 CHF in CMA 2002; Clinical Cardiology 1996; Internal Medicine 2004; NYHA 80 65.4 64.6 47.5 4W Tao X 2011 CHF NA ESC 2008 100 NA NA 0 4W Tian Y 2011 diastolic heart NA ESC criteria; MoH 2002 100 58.0 ± 8.2 58.0 ± 8.5 47 1M Wang N 2014 CHF in or out MoH 2002 54 55-75 58-76 53.7 8W Wang Q 2012 CHF in or out NYHA 80 40-70 41-70 61.25 24W Wang SZ 2012 HF NA Diabetic Cardiomyopathy 60 60 ± 13 60 ± 11 61.67 4W 2010; NYHA Wang YY 2013 chronic congestive in or out NYHA 79 62.6 ± 2.4 61.4 ± 2.3 53.16 4W Wei XB 2013 CHF in NYHA; ACC/AHA 2009 84 87 ± 6 100 12W Wen Y 2012 CHF NA CMA 2007; NYHA 90 70.4 ± 5.6 57.78 1M Wu GL 2015 CHF out CMA 2007; NYHA 104 67.5 ± 6.8 66.7 ± 7.1 64.32 2M Wu SP 2014 CHF in or out CMA 2014 130 52.2 ± 5.8 53.8 ± 7.3 73.8 4W Wu Xian 2014 CHF in CMA 2007 60 64.47 ± 8.23 63.57 ± 8.94 55.38 4W Xiong SQ 2014 CHF in CMA 2007; NYHA 80 61.2 ± 7.11 62.3 ± 7.45 52.5 6W Xu GS 2014 CHF NA NYHA 64 55.7 ± 14.0 53.6 ± 15.0 59.38 120D Xue L 2014 CHF in A list of clinical manifestation 124 42-86 64.52 8W Xue LX 2008 chronic congestive in or out AHA criteria 80 56.9 ± 7.3 57.0 ± 7.6 65 8W Yan KL 2012 CHF in Practical Internal Medicine 120 65.2 ± 17.5 56.67 12W 2009; NYHA Yang DK 2014 CHF in NYHA 60 66.0 ± 12.06 65.8 ± 11.33 63.33 4W
Sun et al. BMC Complementary and Alternative Medicine (2016) 16:201 Page 8 of 13 Table 1 Characteristics of included studies (Continued) Yang F 2007 CHF NA ESC 2005 128 66.0 ± 14.0 65.0 ± 15.0 56.25 8W Yang HT 2012 CHF in Clinical Cardiology 1999; 100 58.5 ± 7.0 59 ± 7.6 57 4W NYHA Yang HT 2013 CHF in Clinical Cardiology 1999 100 58.5 ± 7.0 59 ± 7.6 57 4W Yang J 2013 CHF NA CMA 2007; NYHA 90 56.8 ± 4.3 C1 (57.2 ± 4.1) 43.33 12W C2 (57.1 ± 3.9) Yang W 2012 CHF in CMA 2007; NYHA 80 60.52 ± 12.6 62.7 ± 9.6 56.25 4W Yao L 2011 CHF in CMA 2007; NYHA 102 52 ± 11 56 ± 9 52.94 8W Ye RS 2013 CHF NA CMA 2007; NYHA 80 65-92 65-90 56.25 6M Ye S 2012 CHF in CMA 2007; NYHA 114 60.29 ± 5.62 53.51 3M Yin ZL 2009 congestive heart in Framingham criteria; NYHA 50 57.4 ± 7.6 66 4W Ying M 2013 CHF NA Framingham criteria; NYHA 80 50-80 52.5 3M Yu JH 2008 diastolic heart in Framingham criteria; 70 65.7 ± 6.1 66.1 ± 8.2 60 12M CHFA 2001; NYHA Yuan JK 2012 HF in NYHA 62 41.65 ± 9.33 43.08 ± 7.55 58.06 4W Zhai N 2015 CHF NA CMA 2014 80 70.6 ± 4.4 61.54 12W Zhang CA 2013 CHF in or out AHA 1995; NYHA 83 59.31 ± 10.19 61.0 ± 8.39 66.27 12W Zhang H 2011 CHF NA ISFC/WHO criteria 123 45-80 50-82 60.16 4W Zhang J 2015 CHF NA Practical Internal 60 63.1 ± 9.5 62.5 ± 8.2 50 4W Medicine 1998,NYHA Zhang R 2014 CHF in CMA 2007; NYHA 80 55.0 ± 10.9 53.0 ± 11.3 62.14 8W Zhang WL 2013 CHF in NYHA 94 47-86 45-87 58.51 4W Zhang XX 2010 left cardiac NA NYHA 136 53.5 52.94 6M insufficiency Zhao JS 2014 CHF NA CMA 2007; NYHA; 450 54.8 ± 4.6 55.3 ± 4.7 48.33 12W MoH 2002 Zhao MJ 2009 HF in or out Framingham criteria; NYHA 68 46-69 45-69 64.71 4W &Zhao MJ 2012 Zheng JJ 2012 CHF in CMA 2007; NYHA 76 64 ± 15 64 ± 14 55.26 6M Zheng LW 2013 CHF in or out CMA 2007; NYHA 164 66.9 ± 11.5 67.8 ± 12.0 53.05 12W Zheng WH 2014 refractory heart NA NYHA 87 63.44 ± 2.20 61.92 ± 2.70 56.32 6W Zhou FZ 2011a congestive heart in NYHA 59 66 69.49 12W Zhou Y 2013 HF NA Internal Medicine 2010 60 56.9 ± 7.3 57.0 ± 7.6 63.33 8W Zhu HG 2012 CHF in or out NYHA 78 63.1 63.4 61.54 3M Zhuo JY 2013 CHF NA NYHA 136 62.74 ± 7.78 61.01 ± 8.12 54.41 4W ACC American College of Cardiology, AHA American Heart Association, C control group, CHF chronic, CHFA Chinese Heart Failure Association, CMA Chinese Medical Association, ESC European Society of Cardiology, HF, ISFC International Society and Federation of Cardiology, ISH International Society of Hypertension, MoH Ministry of Health in China, NA not available, NYHA New York Heart Association, T treatment group, WHO World Health Organization as specified in methods, although only one provided a study protocol. Insufficient information was available for us to conduct a risk of bias assessment in terms of selective reporting. In terms of other biases, only 122 trials reported comparability of baseline data and only one study (Li XL 2013) reported conducting a sample size calculation (Fig. 2). Effects of interventions Qili Qiangxin capsule plus conventional treatment versus conventional treatment Our meta-analysis (Additional file 4)showed that in comparison to conventional treatment alone, Qili Qiangxin plus conventional treatment did not have a statistically significant effect on reducing mortality (RR 0.53, 95 % CI 0.27 to
Sun et al. BMC Complementary and Alternative Medicine (2016) 16:201 Page 9 of 13 Fig. 2 Risk of bias summary 1.07, I 2 = 0 %). Qili Qiangxin plus conventional treatment led to a significant reduction in major cardiovascular events (RR 0.46, 95 % CI 0.34 to 0.64, I 2 =0 %; defined as outpatient visits or re-admission for HF and cardiogenic or all-cause mortality), when separately analyzed, it significantly reduced the outpatient visits (n =1 trial, 60 participants, RR 0.22, 95 % CI 0.05 to 0.94), but did not have a statistically significant effect on reducing cardiogenic mortality (n = 1 trial, 56 participants, RR 0.67, 95 % CI 0.21 to 2.11). Meta-analysis showed a statistically significant reduction in hospitalizations due to HF (RR 0.49, 95 % CI 0.38 to 0.64, I 2 =0 %), and in addition, sensitivity analysis based on consideration of worst-case scenarios revealed that missing data did not change the result of this meta-analysis (RR 0.50, 95 % CI 0.39 to 0.65, I 2 = 0 %). Besides, due to the limited quantity of trials reported major outcomes, we did not carry out subgroup analyses on different types of heart or different durations of treatment. In addition, when compared with conventional treatment alone, Qili Qiangxin plus conventional treatment significantly improved cardiac function (RR 1.38, 95 % CI 1.29 to 1.48, I 2 = 0 %; defined as an increase of two or more functional classes using NYHA) and QOL (MD 8.48 scores, 95 % CI 9.56 to 7.39, I 2 =24 %). Used as an adjunctive treatment, Qili Qiangxin was associated with a lower incidence of adverse events (RR = 0.56, 95 % CI 0.40 to 0.78, I 2 = 19 %). Details are displayed in Table 2. A total of 84 trials evaluated LVEF and were pooled with a random model. Pooled comparisons demonstrated that Qili Qiangxin plus conventional treatment had a statistically significant beneficial effect compared to conventional treatment alone in terms of LVEF (MD 5.87, 95 % CI 5.28 to 6.47). However, a significant degree of heterogeneity was detected (I 2 = 91 %), and when take subgroup analysis on duration of treatment, large heterogeneity still existed. Tests for subgroup differences showed no significant difference in effect between the trials with different treatment duration. Meta-analysis of 24 trials demonstrated that Qili Qiangxin plus conventional treatment significantly reduced levels of NT-proBNP (MD 214.43 pg/ml, 95 % CI 269.42 to 159.45). The high level of heterogeneity (I 2 =96%)inthesetrialshowever should be noted. Similarly, pooled comparison of 42 trials indicated that Qili Qiangxin plus conventional medicine significantly improved the 6MWD (MD 47.21 meters, 95 % CI 44.53 to 49.90) when compared with conventional medicine alone. Again, a considerable level of heterogeneity (I 2 = 96 %) was observed. Considering general low quality of included trials, we did not take sensitivity analyses based on study quality according to protocol. Qili Qiangxin capsule plus conventional treatment versus placebo plus conventional treatment Three trials were identified for this comparison. One multicenter double-blind trial (Li XL 2013) evaluated the composite cardiac events (CCEs) for 491 patients, and reported that CCE rate was 4.51 % in the Qili Qiangxin plus conventional treatment group, compared with 10.93 % in the placebo plus conventional treatment group (p <0.05) [18]. This study also reported a favorable effect of Qili Qiangxin plus conventional treatment on the plasma NT-proBNP level, the NYHA functional classification and QOL by MLHFQ at 12 weeks (p < 0.001 for above outcomes). Meta-analysis of three trials (Fig. 3) showed statistically significant improvement of 6MWD in the Qili Qiangxin plus conventional medicine group compared to placebo plus conventional medicine (MD = 49.55 meters, 95 % CI 38.79 to 60.32, I 2 = 0 %). Qili Qiangxin capsule plus conventional treatment versus medications recommended in guidelines plus conventional treatment Nine trials compared Qili Qiangxin capsule plus conventional treatment to supplementary medications recommended in clinical guidelines. The supplementary
Sun et al. BMC Complementary and Alternative Medicine (2016) 16:201 Page 10 of 13 Table 2 Summary of findings of Qili Qiangxin plus conventional treatment compared to conventional treatment for Outcomes Illustrative comparative risks a (95 % CI) Relative effect (95 % Assumed risk Corresponding risk CI) All-cause mortality or cardiovascular mortality Conventional treatment Qili Qiangxin plus Conventional treatment 72 per 1000 38 per 1000 (20 to 77) RR 0.53 (0.27 to 1.07) Follow-up: 1 to 6 months Major cardiovascular events Follow-up: 3 to 6 months 598 per 1000 275 per 1000 (203 to 383) RR 0.46 (0.34 to 0.64) Hospitalizations due to 342 per 1000 167 per 1000 (118 to 223) RR 0.49 Follow-up: 1 to 6 months (0.38 to 0.64) cardiac function (defined as an increase of two or more functional classes using NYHA) Follow-up: 1 to 6 months Quality of life (QOL) Follow-up: 1 to 12 months 336 per 1000 464per 1000 (434 to 498) RR 1.38 (1.29 to 1.48) The mean QOL in the intervention groups was 8.48 lower (9.56 to 7.39 lower) Adverse drug reaction (ADR) 35 per 1000 20 per 1000 (14 to 27) RR 0.56 (0.40 to 0.78) No of Participants (studies) 539 (6 studies) 224 (3 studies) 669 (9 studies) 4603 (54 studies) 792 (10 studies) 4846 (56 studies) Quality of the evidence (GRADE) low b,c,d moderate b,d moderate b low b,e low b,f moderate b Patient or population: patients with Settings: in or out Intervention: Qili Qiangxin plus Conventional treatment Comparison: Conventional treatment CI confidence interval, RR risk ratio GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate Very low quality: We are very uncertain about the estimate a The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95 % confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95 % CI) b The RCTs failed to reported the methods of randomized and concealment of allocation c This outcome is a clinical endpoint d Total number of events is less than 300 e Most of the trials have wide range of 95 % CI for effect estimate f There was significant statistical heterogeneity among trials according to I 2 test Comments medications included thiazide diuretics, benazepril, captopril, metoprolol, irbesartan, trimetazidine, hydrochlorothiazide and digoxin. Meta-analysis with a fixed model of four trials indicated no significant effect on cardiac function (RR = 1.26, 95 % CI 0.94 to 1.70, I 2 = 4 %) for Qili Qiangxin plus conventional treatment when compared with supplementary medications plus conventional treatment. Further subgroup analyses on cardiac function according to medications found that Qili Qiangxin had no statistically significant differences compared to captopril (n = 2 trials, RR = 1.27, 95 % CI 0.89 to 1.82, I 2 = 0 %), irbesartan plus trimetazidine (n =1 trial, RR = 2.50, 95 % CI 0.83 to 7.49), or digoxin (n =1 trial, RR = 0.85, 95 % CI 0.45 to 1.59).. Meta-analysis with a random model of four trials showed that Qili Qiangxin plus conventional treatment had significantly lower risk of adverse events (RR = 0.21, 95 % CI 0.06 to 0.74, I 2 = 49 %). Two trials reported 6MWD and meta- Fig. 3 Forest plot of Qili Qiangxin plus conventional treatment versus placebo plus conventional treatment
Sun et al. BMC Complementary and Alternative Medicine (2016) 16:201 Page 11 of 13 analysis showed that Qili Qiangxin plus conventional treatment significantly improved 6MWD compared with supplementary medications (MD = 43.29 meters; 95 % CI =14.91 to 71.67, I 2 =58%). Publication bias A funnel plot analysis was generated for 50 trials comparing Qili Qiangxin plus conventional treatment to conventional treatment alone for the outcome of NYHA levels. No asymmetry was observed, suggesting no publication bias (Fig. 4). Discussion Summary of findings The findings of this review suggest that in patients with HF, Qili Qiangxin used as an adjunct to conventional treatment leads to a statistically significant reduction in major cardiovascular events and re-hospitalization due to HF when compared with conventional treatment alone. However, there appeared to be no additional effects of Qili Qiangxin in terms of mortality rate. Qili Qiangxin plus conventional treatment also appears to significant improvements in cardiac function measured by levels of NHYA and showed significant beneficial effects on NTproBNP levels, QOL, LVEF and 6MWD. Pooled data indicated that Qili Qiangxin as an adjuvant treatment have clinical significance in improving exercise capacity as well as symptomatic status. Preliminary data suggests that Qili Qiangxin appears to be safe. However, it should be noted that the majority of included trials had low methodological quality and a high risk of bias. Any conclusions drawn from this review should therefore be interpreted with caution. Strength and limitations This study presents the first comprehensive and rigorous review of Qili Qiangxin as a supplementary treatment for patients with HF. Previous criticisms have been made regarding the use of different terms to describe types of HF potentially being confusing [7]. It is strength of this review that we included all types of HF with different comorbidities in order to maximize the impact and clinical relevance of our findings. There are a number of limitations to this review which need to be acknowledged. The majority of included studies were assessed as unclear risk of bias. This was largely owing to the lack of details, particularly in terms of random sequence generation, allocation concealment, blinding methods and availability of a protocol. Due to limited resources and time constraints we were not able to contact trial authors to request missing data and other information preventing us from being able to make a complete assessment regarding risk of bias. However, the sensitivity analysis indicated that the missing data not change the results in this review. Furthermore, the followup period in the included studies was no longer than six months, with the majority reporting a follow-up of three months or less. This makes it difficult to interpret the present evidence on mortality as an outcome, and in assessing the long-term effects and safety of administering Qili Qiangxin. We excluded 40 articles on the basis of no relevant outcomes reported. These articles did not report Fig. 4 The funnel plot of publication bias
Sun et al. BMC Complementary and Alternative Medicine (2016) 16:201 Page 12 of 13 the outcomes we listed in protocol, instead, they chose composite outcome indicator. We excluded these articles as they failed to provide data of separate components. Considering all studies excluded for this reason reported positive results for the composite outcome, we believed the exclusion was unlikely to affect the results of our review. Previous studies A recent editorial has suggested that Qili Qiangxin showed promising results. If Qili Qiangxin is shown to be safe and effective from further rigorous clinical trials research, this presents an interesting area of further work that may fundamentally challenge our current need to precisely understand the pharmacodynamics of all drug therapies [19]. Herbal medicines appear to operate through a variety of often poorly defined synergistic mechanisms involving multiple chemical components. In our study we found that Qili Qiangxin capsules have a positive effect on NT-proBNP levels. Previous studies showed that NT-proBNP level can be used as a prognostic marker for congestive as decreased NT-proBNP levels predicted reducing mortality in 10 years [20 22]. Levels of NT-proBNP clearly differ among various congenital heart lesions, and a higher level of NT-proBNP correlates with diastolic dysfunction parameters. NTproBNP levels are related to exercise capacity and also increase with the more dysfunctional HF stages [23]. In our study, we included patients regardless of gender, age, etiology, ethnic group, severity, and course of diseases. Consequently the patients in different trials had different underlying diseases. All of these factors might explain the high heterogeneity in the meta-analysis of NT-proBNP. The high heterogeneity of LVEF and 6MWD might separately due to the different population baseline of LVEF and 6MWD in the included trials. Implications for future research The results from this review suggest that further research is warranted in order to provide further evidence assessing the effects and safety of Qili Xiangxin as an adjuvant to conventional treatments for HF. We have a number of recommendations for future research. Various diagnostic criteria are used internationally for HF and future research should ideally use internationally recognized diagnostic criteria such as the ACC/AHA guidelines or ESC guidelines as part of their inclusion criteria. Further studies of Qili Qiangxin should also incorporate a minimum one year follow-up period in order that clinically important data on outcomes such as mortality and cardiac events can be provided. These were rarely reported amongst the RCTs we found in this review and further data in this area would be clinically meaningful to patients and providers. Furthermore, we found the reporting of clinical trial methods such as random sequence generation and allocation concealment inadequate and we recommend researchers report in full their trial methodology in future publications. Linked to this, none of the RCTs we included in this review provided trial protocols, and some did not provide all outcomes that had been described in the methods section. For transparency, we recommend that researchers prospectively register trials, publish trial protocols and cite the protocol or registration number in subsequent publications. This will enable future researchers and guideline developers to consider the evidence presented in light of what had been planned by the research team prior to trial commencement. Finally, we found few RCTs using placebo-control design in this review. Studies in future should adopt a doubleblinded placebo-controlled design in order that further information regarding specific effects of Qili Qiangxin in HF can be provided. Conclusions When compared with conventional treatment alone, Qili Qiangxin combined with conventional treatment demonstrated a significant effect in reducing cardiovascular events and re-hospitalization rate, though not in mortality. Qili Qiangxin appeared to be associated with an increased QOL and preliminary data suggested that it is safe. This data was drawn from low quality trials and the results of this review must therefore be interpreted with caution. Further rigorous research is warranted through large, prospective clinical trials in order to confirm these findings. Additional files Additional file 1: PRISMA 2009 Checklist. (DOC 63 kb) Additional file 2: Supplemental reference list of all included study. (DOC 627 kb) Additional file 3: The risk of bias ratings and rationales for each included study. (DOC 201 kb) Additional file 4: Forest plots for all meta-analyses. (DOC 660 kb) Acknowledgements We would like to thank Dr. Jin Luo for her professional advice. Funding This study was supported by the Program for Innovative Research Team (2011-CXTD-09) of Beijing University of Chinese Medicine, the grant of Research Capacity Building (No. 201207007) from the State Administration of Traditional Chinese Medicine of China. GY Yang and JP Liu was were partially funded by grant number R24 AT001293 from the National Center for Complementary and Alternative Medicine (NCCAM) of the US National Institutes of Health (www.nccam.nih.gov). Availability of data and materials The datasets supporting the conclusions of this article are included within the article.
Sun et al. BMC Complementary and Alternative Medicine (2016) 16:201 Page 13 of 13 Authors contributions JS designed the study, performed the study and drafted the manuscript: KZ extracted and analyzed the data, and participated in the revise of the manuscripts. WJX extracted the data and prepared graphs, GYY helped to analyze the data and revised of the manuscript. YJZ extracted the data, CCW participated in extracting data. LL helped to revise the manuscript and corrected language problems. MH helped to revise the manuscripts. GL helped to correct language problems. JPL conceived of and designed the study and helped to draft the manuscript. All authors read and approved the final manuscript. Competing interest The authors declare that they have no competing interest. Consent to publish Not applicable. Ethics approval and consent to participate Not applicable. 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